Tasimelteon (1) – Hetlioz®

• Clinical trials
  • The SET study – a randomised, double-blind, multicentre, controlled trial investigating the efficacy of tasimelteon in patients with Non-24 – included 84 patients who were randomised in a 1:1 ratio to two treatment arms (20 mg tasimelteon and placebo) and treated for 26 weeks.
  • The randomised, double-blind, multicentre, controlled RESET trial, which investigated the sustained efficacy of tasimelteon in synchronising the circadian rhythm in patients with Non-24, the study included patients who had been screened for or had participated in the SET study.

completely blinded adults for the treatment of non-24-hour sleep-wake syndrome (Non-24)

• non-quantifiable
• The G-BA therefore classifies the extent of the non-quantifiable additional benefit of tasimelteon on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the condition, the written submissions and the oral hearing.
• There is an additional benefit, but it is non-quantifiable because the scientific evidence currently does not permit a quantifiable assessment of the extent of the additional benefit for patient-relevant endpoints.
• mortality
  • Mortality was investigated as an AE in the SET and RESET studies. No deaths occurred in either study.
• Morbidity – change in LQ-nTST (lower quartile of total night-time sleep time) and nTST (total night-time sleep time)
  • Total night-time sleep time (LQ-)nTST was calculated using two questions from the Post-Sleep Questionnaire (PSQ), which patients answered daily in the morning via an Interactive Voice Response system.
  • As the endpoint (LQ-)nTST does not allow conclusions to be drawn about sleep quality, it is assessed as not being relevant to patients on its own. Consequently, no conclusions can be drawn regarding the extent of the additional benefit.
  • However, as the patient relevance of these endpoints has not been assessed, these data cannot be used to determine the extent of the additional benefit.
• Morbidity – Change in UQ-dTSD (upper quartile of total daily sleep duration) and dTSD (total daily sleep duration)
  • Daytime sleepiness is a common symptom in patients with Non-24. Naps (sleep events lasting longer than 5 minutes) may be a sign of daytime sleepiness, but are not necessarily a consequence of the patients’ daytime sleepiness.
  • For this reason, the clinical relevance of the (UQ-)dTSD endpoint cannot be assessed.
  • The difference in the reduction in daytime sleep duration (UQ-dTSD) is –33.51 min [–55.34; –11.68] and –59.25 min [–110.74; –7.77], respectively.
  • However, as the clinical relevance of these endpoints has not been assessed, these data cannot be used to determine the extent of the additional benefit.
• Morbidity – Change in CGI-C (Clinical Global Impression-Change)
  • The CGI-C is used to assess the change in the patient’s overall clinical impression as evaluated by an investigator.
  • In the Non-24 indication, an assessment of the change in health status as part of a patient-reported outcome can be carried out by the patient themselves and is considered more appropriate. An assessment by the investigator is not regarded here as sufficient or relevant to the patient.
• Morbidity – synchronisation of the circadian rhythm
  • The pharmaceutical manufacturer argued that synchronisation of the circadian rhythm can be demonstrated by measuring the concentrations of 6-sulfatoxymelatonin (aMT6s) and cortisol in urine.
  • This surrogate parameter is used in the diagnosis of Non-24 and other sleep disorders associated with the circadian rhythm. However, it has not been validated as a patient-relevant endpoint and is therefore assessed as a non-patient-relevant endpoint.
  • Consequently, no conclusions can be drawn regarding the extent of the additional benefit based on the concentrations of aMT6s and cortisol in urine.
• quality of life
  • No data on quality of life were collected in the SET and RESET studies.
  • Particularly in the indication of Non-24, where the patient’s impairment due to insufficient or poor-quality sleep resulting from a circadian rhythm disorder should be reflected in domains of quality of life, it would be desirable to document these changes in quality of life.
• Side effects
  • With regard to the parameters of adverse events (AEs), moderate or severe AEs and serious AEs, an analysis of the relative frequencies in both studies reveals a disadvantage for tasimelteon compared with placebo.
  • A statistically significant inferiority of tasimelteon was observed only in the incidence of AEs in the SET study.
  • Overall, very few serious AEs or AEs leading to discontinuation of the study medication occurred in either treatment arm of the studies, and there were no deaths.
  • The most common AEs associated with tasimelteon in the SET study were nasopharyngitis (placebo: 9.5% vs. tasimelteon: 7.1%), urinary tract infection (2.4% vs. 7.1%), upper respiratory tract infection (0% vs. 7.1%), nausea (7.1% vs. 2.4%), elevated alanine aminotransferase (4.8% vs. 9.5%), elevated aspartate aminotransferase (4.8% vs. 7.1%), headache (7.1 vs. 16.7 per cent) and peripheral oedema (4.8 vs. 7.1 per cent).
  • In the RESET study, the most common AEs during the pre-randomisation phase were nasopharyngitis (7.0 per cent) and elevated serum creatine phosphokinase. During the randomised discontinuation phase, somnolence, muscle twitching and sleep disturbances occurred more than once whilst on tasimelteon; in contrast, no AEs occurred more than once in the placebo group.
  • Somnolence and sleep disturbances were assessed as being related to the study medication.
  • No withdrawal symptoms were observed upon discontinuation of tasimelteon.
  • Based on the available results on side effects, the extent of the additional benefit of tasimelteon cannot be quantified.
• Overall assessment
  • No conclusions regarding the extent of the additional benefit of tasimelteon can be drawn from the results on mortality, morbidity and side effects reported in the submitted studies.
  • Furthermore, data on quality of life were not collected as part of the studies. It is therefore not possible to assess the extent of the burden on patients caused by desynchronisation.
  • Against this background, it is not possible to assess the extent of the additional benefit.
  • None of the endpoints recorded under the morbidity category in the SET and RESET studies are considered patient-relevant here.
  • Assessing the relevance of tasimelteon’s effect would have required an examination of the sleep quality or quality of life of the patients concerned.

Courtesy translation only, please refer to the German original.